PROJECT SUMMARY The diagnosis and treatment of World Trade Center (WTC) related diseases are a significant public health concern. Although we have discovered molecular determinants of particulate matter (PM) related disease, much remains to be learned about how the variants impact disease. Biomarkers of metabolic syndrome and vascular disease expressed soon after WTC exposure predict development of WTC-Lung Injury (WTC-LI). However, the metabolome remains an untapped resource that has the potential to comprehensively characterize many aspects of WTC-LI. Metabolites have the distinct advantage of being more proximal markers of disease than genomic or meta-genomic changes. Metabolomic profiling, the systematic analysis of all metabolites, has been successful at identifying biomarkers for many diseases. To date, there are few metabolomics studies of particulate lung disease. The overarching hypothesis of this proposal is that metabolomic profiling, integrated with other molecular data, will identify key pathways that elucidate our understanding of WTC-LI and related lung diseases. Metabolomics will not only inform our understanding of disease but of therapeutic interventions. We will 1) IDENTIFY individual metabolites and metabolic profiles associated with WTC-LI using global metabolomic screens in our pilot symptomatic cohort. To improve the prediction models? generalizability, we will 2) VALIDATE biomarker data in less homogeneous groups of WTC exposed FDNY rescue and recovery workers. We will integrate metabolomics data with previously determined biomarkers in the larger WTC cohort. This will allow us to define a targeted biomarker profile that we will use in the treatment phase of this proposal. 3) TREAT. We will identify metabolomic signatures through the integration of environmental, clinical, and targeted metabolomics data. This will be the first metabolomics study in WTC-exposed subjects, enabling the identification of distinctive patterns in individuals with WTC-LI, and motivating specific therapeutic approaches for disease management. Predicting future risk of airway injury can focus monitoring and early treatment on the subset of patients in greatest need of these services. Data generated by this grant will improve the understanding of WTC-LI and enhance our ability to diagnose and treat WTC-related airway injury. The overall goal at the end of four years will be to identify a diet/behavioral intervention that will reduce the burden of disease on health-related quality of life by reducing body mass index and to identify qualified biosignatures that can be modified. Lessons learned from this investigation can be validated in other cohorts who face significant public health concerns due to heavy PM exposure, and who may benefit from the technology-supported behavioral modification methods.